All Patients with ADPKD Should Undergo Screening for Intracranial Aneurysms: CON

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic condition marked by the continuous growth of bilateral kidney cysts.¹ Patients with ADPKD, due to compromised vessel elasticity, have an elevated risk of developing intracranial aneurysms (IAs), which manifest as dilations in major bifurcating brain arteries.² Aberrant polycystin protein expression in these patients results in an IA prevalence 4–5 times higher than the general population.^3–6

A ruptured IA has dire consequences, leading to high mortality and significant morbidity. The ensuing subarachnoid hemorrhage (SAH) is a primary morbidity associated with ADPKD, emphasizing the critical need for SAH prevention to improve patient outcomes. Although effective IA screening and management are crucial, the optimal approach to screening, particularly the target populations and frequency, remains debated.⁷ The pivotal question is whether a diagnosis of ADPKD alone is sufficient grounds for a routine brain magnetic resonance angiography or whether additional risk factors should be considered before initiating screening.

Considering IA screening, alignment with the World Health Organization's principles for presymptomatic detection would be recommended. This alignment demands a profound understanding of disease progression and an agreement on treatment standards. Essential elements to consider include aneurysm prevalence, screening efficiency, cost implications, and the emotional effect on patients (Table 1). Notably, IAs in ADPKD display distinct characteristics concerning risk factors, detection age, and rupture risk. Despite a higher IA prevalence in ADPKD than the general population, rates can fluctuate significantly between 5% and 22%, with some studies suggesting figures as high as 40%, possibly due to case selection bias.

Table 1.

Considerations and challenges associated with universal intracranial aneurysm screening in patients with autosomal dominant polycystic kidney disease

Aspect	Concerns/Details
Aneurysm prevalence and rupture risk	- Variable prevalence of IAs in ADPKD: between 5% and 40% (with higher rates potentially influenced by case selection bias). - Many aneurysms may emerge newly rather than being preexisting. - Low rupture rate in the broader ADPKD population (0.04 per 100 patient-years in targeted screening).
Physical risks	- Risks associated with interventions: EVT has 4.96% risk of clinical complications and 0.30% case-fatality rate, while NST has 8.34% complication rate and 0.10% fatality rate. - Morbidity and mortality tied to surgical treatments are considerable: 2.3% mortality and 15.3% disability rate at 1 mo postsurgery, increasing to 3.8% and 12%, respectively, by the 1-yr mark.
Psychological risks	- Emotional distress and anxiety due to ongoing surveillance of small IAs. - An uptick in depressive symptoms and reduced social engagement in those diagnosed with unruptured IA. - Challenges concerning driving and flying licenses as well as life insurance policies after diagnosis.
Economic ramifications	- The feasibility and benefits of universal screening may differ due to variations in costs, medical expertise, and potential complications across different health care settings and countries. - Some cost-utility analyses may overestimate aneurysm rupture risk.
Other considerations	- The risk of incidental findings during the screening process. - Differences in access to multidisciplinary medical care and variations in local neurosurgical expertise and outcomes. - The need for comprehensive dialog and collective decision making rooted in informed consent.

ADPKD, autosomal dominant polycystic kidney disease; EVT, endovascular treatment; IA, intracranial aneurysm; NST, neurosurgical treatment.

Risk factors play a pivotal role in determining the likelihood of IA development in patients with ADPKD. Influences range from age, familial aneurysm history, the PKD1 genotype, early-onset hypertension, to smoking habits.^4,8,9 These aneurysms tend to manifest roughly a decade earlier in patients with ADPKD,¹⁰ with gender-based risks maintaining consistency until age 50 years.⁹ Beyond that point, women face a heightened risk, likely due to the diminishing protective effects of estrogen.⁹ A family history of IA or SAH is the primary risk factor. Recently, the Number of affected relatives, Age, Smoking, and Hypertension predictive score emerged to estimate IA risk during an initial screening for patients with multiple first-degree relatives with aneurysmal SAH.¹¹ Predictors were the number of affected relatives, older age, smoking, and hypertension.¹¹

Understanding the rupture risk of IAs is also essential. The PHASES score gauges the 5-year rupture risk for presymptomatically detected cerebral aneurysms.¹² This score emerged from an analysis of six prospective cohort studies, encompassing 8382 patients and 10,272 IAs from various regions, including high-risk population, such as Finland and Japan. The findings revealed that the mean rupture risk was 1.4% at 1-year (95% confidence interval, 1.1 to 1.6) and 3.4% at 5-year (95% confidence interval, 2.9 to 4.0) intervals. This study identified six independent predictors for rupture, namely population, hypertension, age, aneurysm size, previous SAH from another aneurysm, and aneurysm site.

Most ADPKD-related aneurysms, predominantly located in large-caliber arteries of the anterior circulation, are small (<6 mm).^13,14 Patients with ADPKD showed a higher rate of IA multiplicity (33.2% versus 23.1%).¹³ Familial aneurysms tend to rupture earlier and at smaller sizes compared with sporadic cases.^15,16 The risk of rupture also depends on the aneurysm's location, particularly in the anterior brain territory.¹⁷ For anterior circulation aneurysms with sizes ranging 7–12 mm, the 5-year rupture rate is 2.6%. This rate escalates to 14.5% for sizes between 13 and 24 mm and jumps to 40% for aneurysms larger than 25 mm. Small IAs in patients with ADPKD can rupture, with 20% of ruptured aneurysms measuring <5 mm, and 33% falling in the 5–9 mm range. This is distinct from the typical pattern in the general population where aneurysms smaller than 7 mm seldom experience rupture.

Although patients with ADPKD have a heightened incidence of aneurysm rupture, the efficacy of universal screening for timely detection remains debated and optimal intervals for brain imaging follow-ups to identify IAs are undetermined. A prevailing theory suggests that most hemorrhages stem from newly emerged aneurysms, not preexisting ones, highlighting the discrepancy between the number of unruptured aneurysms and SAH prevalence. Intriguingly, aneurysms smaller than 10 mm, devoid of hemorrhage history, are believed to manifest only 42 weeks before rupture.¹⁸ ADPKD-related IAs are perceived as stable, mirroring the growth rate observed in the broader population. A mere 30% of those with IAs experience rupture during their lifetime.¹⁷ A comprehensive study spanning from 1989 to 2017 at the Mayo Clinic spotlighting IA screening revealed growth in 13% of instances.⁴ On average, there was a 2±1-mm diameter expansion over a substantial follow-up average of 179±82 months.

The advantages of detecting IAs through a prescreening program to prevent SAH remain ambiguous for the broader ADPKD population. However, within targeted screening programs, such as the Mayo Clinic's previously mentioned series, none of the aneurysms detected through presymptomatic screening led to rupture, resulting in an impressively low rupture rate of 0.04 per 100 patient-years.⁴ A meta-analysis encompassing 15 studies, with 1490 ADPKD participants (showing a 10% prevalence of IAs), recorded an aneurysm rupture rate of 0.13% (on the basis of 792 person-years).¹⁴

Implementing a universal IA screening program comes with several associated risks. While the potential increase in life expectancy through the prevention of SAH is evident, it is essential to determine whether this advantage outweighs the postoperative outcomes of preventative treatments for unruptured IA. A recent meta-analysis evaluated the 30-day risks tied to endovascular treatment and neurosurgical treatment for unruptured IAs.¹⁹ This study synthesized data from 114 studies, incorporating 106,433 patients with 108,263 aneurysms. Endovascular treatment exhibited a 4.96% risk of clinical complications and a 0.30% case-fatality rate, with contributing risk factors, such as female gender, diabetes mellitus, hyperlipidemia, and cardiac issues, among others. Conversely, neurosurgical treatment had an 8.34% complication rate and a 0.10% fatality rate, with contributing factors, such as age, female gender, coagulopathy, and smoking.¹⁹ Interventions are not without their risks. A separate prospective study delved into the morbidity and mortality rates tied to surgical treatments for IAs. The findings highlighted considerable surgical risks: At 1 month postsurgery, mortality stood at 2.3% alongside a 15.3% disability rate, which included an impaired status in 5.5% of patients. By the 1-year mark, mortality increased to 3.8%, with a disability rate of 12%, and an impaired status observed in 5.4% of the participants.²⁰ Thus, it would be prudent not to advocate for universal screening recommendations, as the appropriateness of such screening may vary across regions on the basis of access to multidisciplinary medical care and the nuances of local neurosurgical expertise and outcomes. In some situations, the potential harms of screening might outweigh the benefits, making it counterproductive or even detrimental.

Screening can identify small IAs that, though not immediate treatment candidates, require ongoing imaging surveillance. This can lead to heightened emotional distress and anxiety for the patient. Recent research indicates a correlation between screening and an uptick in depressive symptoms, especially among those diagnosed with an unruptured IA.²¹ A decreased level of social engagement was also observed in this group.²¹ Another study delved into the psychological aftermath of being diagnosed with a minor unruptured IA. It underscored that a sizable fraction of patients grapples with mild anxiety or depression as a direct consequence.²² This emotional toll can be attributed to several factors, including the initial referral, diagnosis process, consultations with neurosurgeons, and ongoing imaging follow-ups. Moreover, the discovery of an unruptured aneurysm can pose challenges concerning driving and flying licenses as well as life insurance policies, the specifics of which may vary by country. Patients must also be apprised of the potential for incidental findings during the screening process.

Beyond clinical and psychological implications, the economic effect of universal screening is vital. The role of cost-utility analyses becomes significant when pondering the adoption of such screening programs. Recent studies have leaned toward universal screening, indicating it provides more quality-adjusted life years than alternatives, such as no screening or targeted screening.^23,24 However, the feasibility and benefits of such programs may differ due to variations in costs, medical expertise, and potential complications of preventive treatments across different health care settings and countries. It is important to note that these cost-utility analyses presume an annual rupture rate that is significantly higher than figures reported in international studies, suggesting a potential overestimation of the aneurysm rupture risk. Thus, although the theoretical benefits of universal screening seem compelling on the basis of cost-utility analyses, real-world implementation may be more nuanced.

A comprehensive dialog on screening risks and benefits, leading to informed collective decision making, is advisable. In this debate article, the authors were tasked to scrutinize the existing data on universal screening. The authors' collective perspective and practice underscore the importance of periodically and thoughtfully reviewing each patient's risks and then weighing the pros and cons of screening on the basis of an individual risk assessment.

In summary, although patients with ADPKD exhibit a heightened risk of IAs, the merits of universal screening for, such aneurysms, remain contested. The variable prevalence rates of IAs, their rate of rupture, the potential physical and psychological risks associated with screening and subsequent interventions, the economic implications, and the nuances of local medical expertise make a universal approach potentially imprudent. The potential harms, in certain situations, could outweigh the benefits. Thus, a tailored, patient-specific approach, which accounts for individual risk factors and the broader medical and socioeconomic context, might be more judicious than blanket screening recommendations.

Disclosures

F. Chebib reports the following: Research Funding: Research grant—Natera Inc., Otsuka pharmaceuticals; Patents or Royalties: Patent no US20200368191A1; and Advisory or Leadership Role: PKD foundation—Chair of Education Advisory Panel. R. Tawk reports the following: Ownership Interest: Medtronic stock ownership: 5-10k; and Research Funding: Medtronic; Microvention.

Funding

None.

Author Contributions

Data curation: Fouad T. Chebib, Rabih G. Tawk.

Formal analysis: Fouad T. Chebib, Rabih G. Tawk.

Methodology: Fouad T. Chebib, Rabih G. Tawk.

Project administration: Fouad T. Chebib.

Resources: Fouad T. Chebib.

Supervision: Fouad T. Chebib.

Validation: Fouad T. Chebib.

Visualization: Fouad T. Chebib, Rabih G. Tawk.

Writing – original draft: Fouad T. Chebib, Rabih G. Tawk.

Writing – review & editing: Fouad T. Chebib, Rabih G. Tawk.